Higher maximal serum concentration of methotrexate predicts the incidence of adverse reactions in Japanese rheumatoid arthritis patients

Shoda, Hirofumi; Inokuma, Shigeko; Yajima, Nobuyuki; Tanaka, Yoshiaki; Oobayashi, Taminori; Setoguchi, Keigo

doi:10.3109/s10165-007-0582-y

Cited by 12 publications

(5 citation statements)

References 7 publications

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“…But, after withdrawal of SASP, all participants showed a higher maximum serum MTX concentration than 0.02 μM. Furthermore, the MTX concentration at baseline in this study was lower than the average serum MTX concentration in Japanese RA patients who received weekly pulse low-dose MTX therapy in a prior study [14], supporting the idea that coadministration of SASP tends to decrease MTX concentration.…”

Section: Discussionsupporting

confidence: 68%

“…SASP was administered orally twice a day (total dosage: 1,000 mg per day). Blood samples were taken 2 h after the first administration of MTX in any given week, because the time-to-maximum serum MTX concentration was reported to be 2.0 ± 0.8 h in the case of oral administration [14]. At baseline (week 0), participants stopped taking SASP, and continued MTX monotherapy, and blood samples were taken 4, 8 and 12 weeks later to measure serum MTX.…”

Section: Methodsmentioning

confidence: 99%

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Drug interaction between methotrexate and salazosulfapyridine in Japanese patients with rheumatoid arthritis

Okada

Fujii

Suga

et al. 2017

J Pharm Health Care Sci

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BackgroundMethotrexate (MTX) and salazosulfapyridine (SASP) are disease-modifying drugs that are commonly used in the treatment of rheumatoid arthritis (RA), and combination therapy with MTX and SASP is recommended for RA patients who show an inadequate response to monotherapy with either drug. This study was designed to examine the interaction between the two drugs from the viewpoint of serum MTX concentration in Japanese RA patients, who were receiving combination therapy with relatively low doses of MTX and SASP.MethodsThis is a 24-week open-label intervention study of stable RA patients (n = 10) with low disease activity. In these patients, who had received SASP/MTX combination therapy for at least 12 weeks, SASP was discontinued, and the patients received MTX monotherapy for the next 24 weeks. The primary outcome was change of serum MTX concentration at 12 weeks after discontinuation of SASP. Two disease activity markers, simplified disease activity index (SDAI) and disease activity score-C reactive protein (DAS28-CRP), were assessed as secondary outcomes at 24 weeks after discontinuation of SASP. We also monitored levels of matrix metalloproteinase-3 (MMP-3) and inflammatory cytokines. Patients were asked to complete a questionnaire after the study.ResultsSerum MTX concentration in RA patients who discontinued SASP increased more than 2-fold within 4 weeks, and the higher level was maintained thereafter. No significant differences were detected in SDAI, DAS28-CRP, MMP-3 or inflammatory cytokines. Most participants reported no change in physical condition after withdrawal of SASP, and most preferred MTX monotherapy for future treatment.ConclusionsWithdrawal of SASP from patients receiving SASP/MTX caused a rapid, marked increase of serum MTX concentration, without any apparent change in disease parameters or side effects. Our results suggest that SASP can be discontinued without adverse effects in stable RA patients receiving combination therapy, at least among Japanese patients receiving relatively low doses of the two drugs.Trial registration UMIN000024507. October 21, 2016 retrospectively registered.

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Section: Discussionsupporting

confidence: 68%

Section: Methodsmentioning

confidence: 99%

Drug interaction between methotrexate and salazosulfapyridine in Japanese patients with rheumatoid arthritis

Okada

Fujii

Suga

et al. 2017

J Pharm Health Care Sci

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“…Leucovorin supplies the active form of folic acid, bypassing DHFR inhibition ( 6 ). In general, the recommended dose of CF rescue is 12–15 mg/m 2 , with an intravenous drip every 6 h, until the MTX concentration falls below 0.01 uM/L ( 28 , 29 ). In this case, the serum MTX concentration was still higher than the aforementioned threshold after 4 days of CF rescue with 20 mg, IV q6h, thus, the dose of CF was elevated to 100 mg, IV q6h.…”

Section: Discussionmentioning

confidence: 99%

Severe Adverse Toxic Effects of Low-Dose Methotrexate Treatment on an Ectopic Pregnancy Patient With Methylenetetrahydrofolate Reductase Mutations: A Case Report

Wang

Liang

et al. 2021

Front. Med.

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Background: Low-dose methylenetetrahydrofolate (LD-MTX) has been widely used for the treatment of the ectopic pregnancy (EP) for many decades, and related severe adverse toxic effects are rare. Current studies have shown that the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene can decrease the MTX clearance, leading to the metabolite accumulation. However, there is a lack of literature report on an MTHFR gene polymorphism associated with adverse toxic effects resulting from the use of LD-MTX in an EP.Case Presentation: We report a rare case of a 38-year-old female who developed persistent fever, grade IV myelosuppression, skin lesions, mucositis, and liver injury after single dose of LDMTX to treat EP. The personalized genetic testing showed that MTHFR TT (677C>T) and MTHFR AA (1298A>C) were detected. Gradually, the symptoms improved after calcium leucovorin (CF) rescue, continuous renal replacement therapy (CRRT), promoting blood system regeneration, and multiple supportive treatments.Conclusion: This is the first report on the serious adverse toxic effects of LD-MTX on an EP patient with MTHFR mutations. We aim to alert obstetricians and gynecologists to this rare condition. The unexpected life-threatening toxicity with LD-MTX should be highly considered and recognized early. In particular, some easily overlooked gastrointestinal, skin, and mucosal symptoms occur earlier than severe myelosuppression. When toxic effects are suspected, detecting the polymorphisms of an MTHFR gene and monitoring MTX concentration in blood could assist us to formulate individualized and active treatments.

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“…Asai S et al, in a cross-sectional study in Japanese patients (Median age: 64), observed that MTX doses >8 mg/wk increased the risk of reflux and abdominal pain (OR: 1.62 and 1.62, respectively); however, association between these AEs and MTX suspension was not analyzed [29]. Shoda H. et al performed a cohort in Japanese RA patients (mean age: 60.8), comparing the maintenance dose of MTX in patients who had AEs vs. RA patients without AEs, identifying a relation between higher doses and AEs (9.6 ± 4.2 mg/wk vs. 6.7 ± 3.0 mg/wk respectively, p = 0.03) [30]. These data support our results of a higher risk of withdrawals of this DMARD related to higher doses.…”

Section: Risk Factors Associated With Mtx Suspension Due To Aesmentioning

confidence: 99%

Risk Factors Associated with Adverse Events Leading to Methotrexate Withdrawal in Elderly Rheumatoid Arthritis Patients: A Retrospective Cohort Study

Avalos-Salgado,

Gonzalez-Lopez,

Gonzalez-Vazquez

et al. 2024

JCM

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Background: Rheumatoid arthritis (RA) in elderly population represents a challenge for physicians in terms of therapeutic management. Methotrexate (MTX) is the first-line treatment among conventional synthetic-disease-modifying anti-rheumatic drugs (cs-DMARDs); however, it is often associated with adverse events (AEs). Therefore, the objective of this study was to identify the incidence and risk factors of MTX discontinuation due to AEs in elderly patients with RA in a long-term retrospective cohort study. Methods: Clinical sheets from elderly RA patients taking MTX from an outpatient rheumatology consult in a university centre were reviewed. To assess MTX persistence, we used Kaplan–Meir curves and Cox regression models to identify the risk of withdrawing MTX due to adverse events. Results: In total, 198 elderly RA patients who reported using MTX were included. Of them, the rates of definitive suspension of MTX due to AEs were 23.0% at 5 years, 35.6% at 10 years and 51.7% at 15 years. The main organs and system involved were gastrointestinal (15.7%) and mucocutaneous (3.0%). Factors associated with withdrawing MTX due to AEs were MTX dose ≥ 15 mg/wk (adjusted HR: 2.46, 95% CI: 1.22–4.96, p = 0.012); instead, the folic acid supplementation was protective for withdrawal (adjusted HR: 0.28, 95% CI: 0.16–0.49, p < 0.001). Conclusions: Higher doses of MTX increase the risk of withdrawals in elderly RA, while folic acid supplementation reduces the risk. Therefore, physicians working in therapeutic management for elderly patients using MTX must focus on using lower MTX doses together with the concomitant prescription of folic acid.

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Higher maximal serum concentration of methotrexate predicts the incidence of adverse reactions in Japanese rheumatoid arthritis patients

Cited by 12 publications

References 7 publications

Drug interaction between methotrexate and salazosulfapyridine in Japanese patients with rheumatoid arthritis

Drug interaction between methotrexate and salazosulfapyridine in Japanese patients with rheumatoid arthritis

Severe Adverse Toxic Effects of Low-Dose Methotrexate Treatment on an Ectopic Pregnancy Patient With Methylenetetrahydrofolate Reductase Mutations: A Case Report

Risk Factors Associated with Adverse Events Leading to Methotrexate Withdrawal in Elderly Rheumatoid Arthritis Patients: A Retrospective Cohort Study

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